Obesity is a disease that affects approximately one third of the population in the United States, and which has become a serious problem in many other countries. Over 60 percent of the American population may be characterized as being either overweight or obese. Obesity and the condition of being overweight both contribute substantially to the risk of morbidity from hypertension, dyslipidemia, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnea, respiratory problems and a wide range of cancers including endometrial, breast, prostrate, and colon cancer. Obesity is associated with increases in deaths from all causes.
Obesity is a complex disease with both genetic and environmental contributions. It increases steadily with age for both men and women, and the age groups with the highest prevalence are men aged 65 to 74 years and women aged 55 to 64 years. Obesity carries with it not only important health consequences, but it can also have a social impact on individuals who may experience stigmatization and discrimination in a variety of situations.
A wide variety of options currently exist for managing and treating obesity. Examples of such options include dietary therapy, increased physical activity, behavior therapy, surgery, and pharmacotherapy. The general goals of treatment include prevention of further weight gain, reduction of body weight, and maintenance of body weight over the long term. A number of drugs are currently approved for use in treating obesity in the United States. Examples of such drugs include those that act by blocking dietary fat absorption (e.g. Oristat) and those that suppress appetite (e.g. Phentermine, Sibutramine). The safety and effectiveness of such medications has not been established beyond one year. All prescription medications used to treat obesity with the exception of Oristat are considered controlled substances. There is a clear need for new classes of efficacious and safe drugs and medicaments for use in treating and preventing obesity.
Adipocytes are the major cellular component in adipose tissue. Adipocytes thus play a key role in the development of obesity. The increase in adipose tissue in obesity is believed to represent the expansion both in the size and number of adipocytes. The active hormonal form of vitamin D, 1α,25-dihydroxy-cholecalciferol (calcitriol) has been reported to inhibit the differentiation of cultured preadipocytes. Sato, M., et al., A. J. Cell. Phys., 135, 545-550 (1988). The structure of calcitriol is shown below and includes the numbering scheme of the carbon atoms used in such compounds and related analogs.
